Accompanying with changes in social lifestyle and aging of society, the overall number of patients with psychoneurotic disorders tends to increase. For example, at present the number of patients with Alzheimer's disease, which is known as a representative neurodegenerative disease, is estimated to be 1.5 million in Japan and 4.0 million in the U.S. According to a prediction, this number increases with an increase in aged people in countries centering around developed countries, and in 25 years, approximately 22 million people throughout the world will suffer from this disease. Currently, in the cognitive dysfunction of Alzheimer's disease (so-called dementia), the involvement of dysfunction of the acetylcholinergic nervous system in the brain has been clarified on the basis of many neuropathological findings, and therefore an inhibitor of acetylcholine degrading enzyme (cholinesterase inhibitor) is clinically used. However, it is hard to say that the inhibitor is sufficiently therapeutically effective. Practically, there is almost no effective method for the prevention and treatment of the disease.
On the other hand, schizophrenia occurs in approximately 1% of the population regardless of race and geographic area, and this is a psychoneurotic disorder, the onset of which often occurs in young generations from adolescence to the age of 20-29. The number of hospital patients with schizophrenia in Japan accounts for approximately 15% of the total number of hospital beds, resulting in a significant problem in terms of medical cost. As symptoms of schizophrenia, there are positive symptoms such as hallucination and delusion, negative symptoms such as flat or blunted emotion, lack of motivation and social withdrawal, as well as cognitive dysfunction. Among these symptoms, cognitive dysfunction may possibly be a core symptom of schizophrenia, and is considered to deteriorate the quality of life (QOL) of patients. Pharmacological therapy is essential for the treatment of schizophrenia, and pharmaceutical agents such as phenothiazine compounds, butyrophenone compounds, benzamide compounds, iminodibenzyl compounds, thiepine compounds, indole compounds and serotonin-dopamine receptor blockers are administered. However, although these pharmaceutical agents actually used in clinical sites are effective for positive symptoms such as hallucination and delusion, they show almost no effect on cognitive dysfunction. Thus, the development of therapeutic agents for cognitive dysfunction has been awaited in Japan and abroad.
Meanwhile, acetylcholine is one of the major neurotransmitters of the central nervous system, and is known to play an important role in the regulation of nervous activities in the cerebral cortex and hippocampus. In recent years, it is speculated that α7 subtype of nicotinic receptor (α7 nicotinic receptor) is involved in the pathological conditions of psychoneurotic diseases such as schizophrenia and Alzheimer's disease.
For example, in the brain (cerebral cortex and hippocampus, etc.) of a schizophrenic patient at autopsy, a decrease in the number of α7 nicotinic receptors has been reported. It is also reported that an abnormality in P50 auditory evoked potential observed in schizophrenic patients is improved by the administration of nicotine, and that α7 nicotinic receptors are involved in this phenomenon (refer to Non-patent documents 1-6).
Similarly, in the cerebral cortex and hippocampus of patients with Alzheimer's disease at autopsy, a decrease in the number of nicotinic receptors (α4β2 nicotinic receptors and α7 nicotinic receptors) has been reported (refer to Non-patent documents 7-9). In addition, it is reported that the amount of α7 nicotinic receptor mRNA of the lymphocytes in Alzheimer's patients is significantly higher than that in normal subjects (refer to Non-patent document 10). It is also reported that the amount of α7 nicotinic receptor mRNA in the hippocampus of Alzheimer's patients is significantly higher than that in normal subjects (refer to Non-patent document 11). In this report, no difference in the amount of mRNA in other subtypes (α3 and α4) was observed between the brain of Alzheimer's patients and the brain of normal subjects, suggesting that α7 nicotinic receptors play an important role in the pathological condition of Alzheimer's disease (refer to Non-patent document 12).
As described above, α7 nicotinic receptors in the brain have been speculated to play an important role in psychoneurotic disorders such as schizophrenia and Alzheimer's disease. However, although several compounds including tropisetron and GTS-21 which affect α7 nicotinic receptors are known at present (refer to Non-patent document 13), no pharmaceutical agent that has improving effects on these psychoneurotic disorders, and also has pharmacokinetic features of resistance to administration to humans as well as safety, has been reported; in addition, in the above-mentioned non-patent document 13, no specific action of tropisetron on psychoneurotic disorders such as schizophrenia and Alzheimer's disease, in particular on cognitive dysfunction, has been described. Furthermore, with respect to tropisetron, this is originally used as an antiemetic agent having an antagonistic action against serotonin 5-HT3 receptor, and this kind of pharmaceutical agent is not known to be used for the prevention and treatment of psychoneurotic disorders. Thus, a pharmaceutical agent effective to humans to such an extent that it can be actually used for the prevention and treatment of psychoneurotic disorders such as schizophrenia and Alzheimer's disease, and in particular psychoneurotic disorders with cognitive dysfunction, has not yet been known to date.    [Non-patent document 1] Freedman R, Adler L E, Bickford P, Byerley W, Coon H, Cullum C M, Griffith J M, Harris J G, Leonard S, Miller C, et al. Schizophrenia and nicotinic receptors. Harvard Reviews of Psychiatry, 2:179-192, 1994.    [Non-patent document 2] Leonard S, Adams C, Breese C R, Adler L E, Bickford P, Byerley W, Coon H, Griffith J M, Miller C, Myles-Worsley M, Nagamoto H T, Rollins Y, Stevens K E, Waldo M, Freedman R. Nicotinic receptor function in schizophrenia. Schizophrenia Bulletin, 22:431-445, 1996.    [Non-patent document 3] Adler L E, Olincy A, Waldo M, Harris J G, Griffith J, Stevens K, Flach K, Nagamoto H, Bickford P, Leonard S, Freedman R. Schizophrenia, sensory gating, and nicotinic receptors. Schizophrenia Bulletin, 24:189-202, 1998.    [Non-patent document 4] Jones S, Sudweeks S, Yakel J L. Nicotinic receptors in the brain: correlating physiology with function. Trends in Neurosciences, 22:555-561, 1999.    [Non-patent document 5] Freedman R, Adams C E, Leonard S. The alpha7-nicotinic acetylcholine receptor and the pathology of hippocampal interneurons in schizophrenia. J Chem Neuroanat 20: 299-306, 2000.    [Non-patent document 6] NeuroReport, 10:1779-1782, 1999.    [Non-patent document 7] Journal of Neurochemistry, 46:288-293, 1986.    [Non-patent document 8] Alzheimer's Disease Reviews, 3:20-27, 1998.    [Non-patent document 9] Alzheimer's Disease Reviews, 3:28-34, 1998.    [Non-patent document 10] Alzheimer's Research, 3:29-36, 1997    [Non-patent document 11] Molecular Brain Research, 66:94-103, 1999.    [Non-patent document 12] Review: Japanese Journal of Neuropsychopharmacology 22: 49-53, 2002.    [Non-patent document 13] Macor J. E. et al., Bioorganic & Medicinal Chemistry Letters, 11, 319-321, 2001.